Sunitinib base, N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidine)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, of the following formula:
can be used as an intermediate in the preparation of sunitinib salts, such as sunitinib malate of the following formula:

Sunitinib malate is a multi-kinase inhibitor marketed in the United States under the trade name SUTENT® by Pfizer, Inc. SUTENT® is approved by the FDA for the treatment of gastrointestinal stromal tumor after disease progression on or intolerance to imatinib mesylate and for the treatment of advanced renal cell carcinoma. SUTENT® is available as hard-shell capsules containing an amount of sunitinib malate that is equivalent to 12.5 mg, 25 mg, or 50 mg of sunitinib. The capsules contain sunitinib malate together with the inactive ingredients mannitol, croscarmellose sodium, povidone (K-25) and magnesium stearate.
U.S. Pat. No. 6,573,293 (“293 patent”) refers to the preparation of sunitinib base and salts thereof, as well as the use of these salts. The '293 patent refers to the synthesis of sunitinib base by condensing 5-formyl-2,4-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide with 5-fluoro-1,3-dihydro-indol-2-one in ethanol in the presence of pyrrolidine. See '293 patent, col. 204,11. 33-50 (example 80, alternative synthesis). The sunitinib base thus prepared was isolated from the reaction mixture by filtration, washed with ethanol, slurried in ethanol, isolated from the slurry by filtration, washed with ethanol, and dried under vacuum to give an orange solid. See id.
U.S. Pat. No. 7,119,209 (“'209 patent”) also refers to the preparation of sunitinib base. The '209 patent refers to the preparation of sunitinib base by reacting 4-(1H-imidazol-1-ylcarbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde, N, N-diethylethylenediamine, and 5-fluorooxindole in acetonitrile in the presence of triethylamine. See '209 patent, col. 15, II. 1-36. The sunitinib base thus prepared was isolated from the reaction mixture by filtration, washed with acetonitrile, and dried under vacuum.
U.S. Publication No. 2003/0069298 and U.S. Publication No. 2007/0191458 refer to the preparation of sunitinib L-malate by reacting Sunitinib base, L-malic acid and a solvent. In addition, it is also disclose forms I (also referred to herein as “Form 1”) and II thereof.
Crystalline, sunitinib malate form I is characterized by diffraction peaks at about 13.2 and 24.2 degrees two-theta, and more preferably, at about 13.2, 19.4, 24.2, and 25.5 degrees two-theta, and most preferably, as listed at table 1 for crystal form I, in a powder X-ray diffraction pattern.
Crystal Form ITwo ThetaRelative(deg.)Intensity11.39711.90713.168215.922716.792517.182419.407620.302021.263121.682822.134822.912124.1710025.467926.062326.962627.5628
The present invention offers: a new salt of Sunitinib, Sunitinib acetate, which can be used as a useful intermediate for the preparation of Sunitinib malate; processes for preparation thereof and its conversion to crystalline Sunitinib malate form I. In addition, the present invention offers other processes for the preparation of Sunitinib malate form I.